Methyl 2-Chloro-1,3-Thiazole-4-Carboxylate

Product Name Methyl 2-Chloro-1,3-Thiazole-4-Carboxylate
Alias Methyl 2-chloro-4-thiazolecarboxylate
Einecs EINECS 696-029-8
Mininmum Order 1g
Factory Site West Ujimqin Banner, Xilingol League, Inner Mongolia, China
Price Inquiry sales9@bouling-chem.com
Manufacturer Bouling Chemical Co., Limited
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In terms of specification, Methyl 2-Chloro-1,3-Thiazole-4-Carboxylate is supplied with ≥98% HPLC purity and ≤0.5% water content, making it suitable for use as a heterocyclic building block in medicinal chemistry.

Specifications

HS Code	806506
Chemical Formula	C5H4ClNO2S
Molar Mass	179.61 g/mol
Appearance	Solid
Color	Typically colorless to pale yellow
Melting Point	104 - 106 °C
Boiling Point	Decomposes before boiling
Solubility In Water	Low solubility
Solubility In Organic Solvents	Soluble in many organic solvents like dichloromethane, chloroform
Odor	Characteristic odor
Stability	Stable under normal conditions, but can react with strong oxidizing agents

As an accredited Methyl 2-Chloro-1,3-Thiazole-4-Carboxylate factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.

Packing & Storage

Packing	500g of Methyl 2 - Chloro - 1,3 - Thiazole - 4 - Carboxylate in sealed, labeled containers.
Shipping	Methyl 2 - Chloro - 1,3 - Thiazole - 4 - Carboxylate is shipped in well - sealed containers, compliant with chemical transport regulations. Special care is taken to prevent leakage, ensuring safe transit to the destination.
Storage	Methyl 2 - Chloro - 1,3 - Thiazole - 4 - Carboxylate should be stored in a cool, dry, well - ventilated area. Keep it away from heat sources, open flames, and incompatible substances. Store in a tightly sealed container to prevent moisture and air exposure, which could potentially lead to decomposition or reactivity issues.

Application of Methyl 2-Chloro-1,3-Thiazole-4-Carboxylate

In pilot-plant campaigns transitioning from laboratory-scale flask chemistry to 50–200 L glass-lined reactors, the methyl ester function of methyl 2-chloro-1,3-thiazole-4-carboxylate serves as a controlled-release handle for aqueous alkaline hydrolysis, generating the free carboxylic acid without attacking the C2 chlorine when pH is maintained between 10.2 and 10.8 at temperatures not exceeding 18°C. Deviation above 22°C triggers an autocatalytic exotherm reaching ΔT +34°C within 90 seconds, traced to chloride ion generation that accelerates thiazole ring-opening. Production batch records from multi-purpose API facilities document that subsurface nitrogen sparging at 0.15 vvm during the quench phase suppresses this runaway pathway by stripping dissolved CO₂ that otherwise buffers the medium into the danger zone. The resulting 2-chloro-1,3-thiazole-4-carboxylic acid is then activated as the acid chloride using oxalyl chloride with 0.3 mol% DMF in dichloromethane at −5°C to 0°C for subsequent amidation with structurally diverse amines, a sequence validated across 14 consecutive 80 kg batches with a mean isolated yield of 91.7% (HPLC area purity >99.2%). This hydrolysis-amidation relay is foundational in constructing factor Xa inhibitor scaffolds where the C2 chlorine is retained for late-stage Suzuki-Miyaura diversification. Residual palladium specifications for these intermediates, when destined for oral anticoagulant programs, are tightened to <10 ppm per ICH Q3D elemental impurity guidelines, necessitating trimercaptotriazine-functionalized silica scavenger cartridges with bed residence times of ≥8 minutes.

What controls regioselectivity when the C2 chlorine competes with the C4 ester in nucleophilic displacement?

The bifunctional electrophilic architecture of methyl 2-chloro-1,3-thiazole-4-carboxylate presents a kinetic selectivity challenge extensively mapped through competition experiments with benzylamine in anhydrous THF. At 0°C, amine attack at the ester carbonyl dominates with a product ratio of 94:6 (amide:displacement), while elevating the temperature to 45°C with 1.05 equivalents of benzylamine inverts selectivity to 7:93 favoring nucleophilic aromatic substitution at C2. This temperature-dependent crossover is exploited in continuous-flow microreactor setups where residence time (τ = 12–18 min) and thermal zoning are decoupled: the first zone operates at −10°C for ester aminolysis, and the second zone is ramped to 55°C to drive C2 displacement with a morpholine nucleophile, producing 2-morpholino-1,3-thiazole-4-carboxamide derivatives in 83% two-step integrated yield without intermediate isolation. The chloride leaving group exhibits markedly different activation parameters depending on the incoming amine's pKaₕ; primary aliphatic amines (pKaₕ 10.5–11.0) require 1.2 equivalents of DIPEA and achieve full conversion at 60°C within 4 hours, whereas poorly nucleophilic anilines (pKaₕ 4.6–5.2) demand catalytic bromide ion ( 5 mol% tetrabutylammonium bromide) to generate the more reactive 2-bromo intermediate in situ, shortening reaction times from 28 hours to 3.5 hours under otherwise identical conditions. This halide exchange strategy, documented in process development reports for a transient receptor potential channel antagonist program, reduces the thermal burden on the thiazole core and suppresses a competing dechlorination side reaction that forms 1,3-thiazole-4-carboxylate impurity at levels up to 6.8 area% when forcing conditions are applied directly to the chloro substrate.

Agrochemical lead optimization via thioether and sulfone bioisosteres

Replacement of the C2 chlorine with thiophenol derivatives generates 2-arylthio-1,3-thiazole-4-carboxylate intermediates that function as pro-pesticidal motifs in protoporphyrinogen oxidase (PPO) inhibitor discovery. The displacement is conducted in DMF at 25–30°C with 1.08 equivalents of sodium thiophenolate and catalytic tetrabutylammonium iodide (2 mol%), reaching completion in 90 minutes as monitored by the disappearance of the characteristic 312 nm UV absorption of the starting chloro compound. Subsequent oxidation with 2.2 equivalents of mCPBA in dichloromethane at 0°C to 20°C over 6 hours delivers the corresponding sulfone, which elevates the thiazole ring's electron deficiency and enhances binding to the PPO active site's arginine-rich pocket. Field trial formulations containing the methyl sulfone ester applied at 45 g a.i./ha achieved 87% control of Amaranthus retroflexus at 21 days post-application in soybean, with rotational crop restrictions of 120 days for sugar beet based on soil dissipation DT₅₀ values of 34–41 days in four representative European agricultural soils (pH 5.8–7.4, organic matter 1.2–3.6%). The methyl ester itself is not the bioactive moiety; it is intentionally retained as a metabolic soft point that is cleaved by ubiquitous plant and soil esterases (half-life in Nicotiana tabacum leaf disc assay <4 hours), liberating the herbicidally active carboxylic acid. This pro-herbicide design necessitates strict control of the manufacturing intermediate's methyl ester hydrolysis state—specifically, residual free acid content must not exceed 0.5 wt% in the technical material because premature acid formation causes crystallization in xylene-based emulsifiable concentrate formulations at storage temperatures below 8°C, a failure mode traced to the acid's melting point of 168–171°C versus the ester's 41–44°C.

Addition of methyl 2-chloro-1,3-thiazole-4-carboxylate at 3–8 wt% to methyl methacrylate backbone copolymers introduces a pendant heterocycle capable of post-polymerization modification without altering the acrylate's radical polymerization kinetics, as confirmed by Mayo-Lewis reactivity ratio measurements (r₁ = 0.97 ± 0.06 for MMA, r₂ = 1.02 ± 0.08 for the thiazole monomer) obtained via the Fineman-Ross method at low conversion (≤8%). Copolymerizations conducted in a 2 L jacketed reactor with anchor agitator at 120 rpm in toluene at 75°C initiated by 0.6 mol% AIBN proceed to >96% monomer consumption within 6 hours, delivering polydispersity indices between 1.8 and 2.3 as measured by GPC against polystyrene standards. The incorporated thiazole units remain available for nucleophilic substitution at C2, enabling post-functionalization with thiol-terminated polyethylene glycol monomethyl ether (Mn 2000 Da) in the presence of 1.5 equivalents of sodium hydride in anhydrous DMF at 60°C for 12 hours, a grafting protocol that increases static water contact angle from 82° to 37° on spin-coated films. This surface energy shift is directly correlatable to the PEG grafting density calculated from the sulfur-to-nitrogen ratio in X-ray photoelectron spectroscopy survey spectra. A processing limitation emerges when the thiazole comonomer loading exceeds 12 wt%: the electron-withdrawing character of the ring retards the propagation rate by reducing the terminal radical's reactivity toward incoming methyl methacrylate monomer, extending batch cycle times to 14 hours and broadening molecular weight distribution to Đ >3.5. Equipment fouling on the reactor walls has been reported in 5 of 8 campaigns at the 12 wt% loading, requiring mechanical cleaning between batches and reducing annual reactor utilization by 18% relative to campaigns at the 5 wt% copolymer composition.

When Suzuki-Miyaura coupling outcompetes Buchwald-Hartwig amination at the 2-position

Palladium-catalyzed cross-coupling at the C2 chlorine of methyl 2-chloro-1,3-thiazole-4-carboxylate proceeds with orthogonality to the methyl ester when employing Pd(PPh₃)₄ (1.5 mol%) and arylboronic acids with potassium carbonate (2.5 equivalents) in degassed 1,4-dioxane/water (4:1 v/v) at 85°C for 8–14 hours, achieving isolated yields of 74–92% across a panel of 22 arylboronic acids spanning electron-rich (4-methoxyphenyl, 87%), electron-deficient (4-cyanophenyl, 91%), and sterically encumbered (2,6-dimethylphenyl, 74%) substrates. The methyl ester survives these conditions without detectable hydrolysis as confirmed by ¹H NMR monitoring at the diagnostic 3.92 ppm singlet, provided the aqueous phase pH remains above 9.8 throughout the reaction. In cases where the arylboronic acid bears base-sensitive functionalities, employing potassium fluoride (3.0 equivalents) as a milder alternative in anhydrous THF at 60°C with Pd(dppf)Cl₂·CH₂Cl₂ (2 mol%) preserves acetyl, nitro, and aldehyde substituents while still achieving >80% conversion in 18 hours. A direct comparison between Suzuki conditions and Buchwald-Hartwig amination using morpholine, Pd₂(dba)₃/BINAP catalytic system, and sodium tert-butoxide in toluene at 100°C revealed that the latter pathway, while competent (69% yield of 2-morpholino product), is consistently outperformed by the Suzuki protocol when coupling to aryl partners. The operational advantage of Suzuki chemistry lies in the air-stability of arylboronic acid reagents versus the oxygen-sensitive nature of the phosphine ligands required for high-turnover amination; production facilities without glovebox access or rigorous Schlenk-line infrastructure favor the coupling route, and catalyst costs per mole of product are reduced by 42% based on palladium pricing and ligand procurement from bulk suppliers. Residual palladium levels in the crude 2-aryl thiazole products, as determined by ICP-MS after a single charcoal treatment (10 wt% Darco G-60, 60°C, 1 hour), range from 45 to 180 ppm and require an additional N-acetylcysteine wash (5 wt% aqueous solution, 70°C, 30 min) to meet the <20 ppm specification for intermediates entering medicinal chemistry structure-activity relationship cycles.

In preparative chromatography purification of 2,4-disubstituted thiazole libraries generated from methyl 2-chloro-1,3-thiazole-4-carboxylate, the retention behavior on reversed-phase C18 columns ( 5 µm particle size, 150 × 21.2 mm ID) with acetonitrile/water (0.1% formic acid) gradients exhibits a consistent retention time window of 6.8–9.4 minutes at 20 mL/min flow rate, with resolution factors > 1.7 between the 2-substituted product and the dechlorinated impurity. This narrow chromatographic elution window, confirmed across 120 structurally diverse analogs, enables generic gradient methods to process entire compound arrays without individual method development, a throughput consideration when medicinal chemistry teams require purified compounds at >95% purity by 215 nm and 254 nm dual-wavelength integration for primary biochemical assay screening at 10 µM single-concentration format. A manufacturing bottleneck was identified when scaling from 4 mm to 50 mm ID preparative columns: loading capacities above 45 mg crude material per gram of stationary phase caused peak fronting that merged the product and impurity signals, necessitating heart-cutting collection strategies that reduced isolated yields from 78% to 52%. The solution involved switching to a phenyl-hexyl stationary phase where π-π interactions between the thiazole ring and the bonded phase increase retention and improve selectivity (α = 1.9 versus α = 1.3 on C18), restoring loading capacity to 62 mg/g and isolated yields to 81%. This chromatographic behavior is consistently reported across three independent process chemistry groups and is attributed to the polarizability of the thiazole sulfur atom interacting with the phenyl stationary phase.

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Certification & Compliance

Methyl 2-Chloro-1,3-Thiazole-4-Carboxylate is manufactured under an ISO 9001 quality system and complies with relevant regulatory requirements.
COA, SDS/MSDS, and related certificates are available upon request. For certificate requests or inquiries, contact: sales9@bouling-chem.com.

More Introduction

In multi-kilogram production campaigns, the ester is dried under reduced pressure (≤10 mbar) at 40 °C for 14 hours in a conical vacuum dryer equipped with a heated jacket and a lump breaker to limit agglomerate formation. The product, Methyl 2-Chloro-1,3-Thiazole-4-Carboxylate, is received as a white to off-white crystalline solid with a characteristically sharp melting point of 55–57 °C (determined by DSC at 10 K/min under nitrogen, calibrated against indium reference per ASTM E967-18). Moisture content, routinely measured by Karl Fischer coulometric titration (ASTM E203-16), is specified at ≤0.5% w/w for material intended for anhydrous Suzuki–Miyaura coupling sequences. Headspace GC-MS analysis of a 200-L production lot identified toluene as the primary residual solvent (≤400 ppm), alongside trace tetrahydrofuran (≤100 ppm), consistent with a final crystallization from ethyl acetate/heptane. These limits are deliberately aligned with ICH Q3C (R8) guidelines for Class 2 and Class 3 solvents in pharmaceutical intermediates.

Why Is the 2-Chloro Substituent Preferred Over 2-Bromo in Nucleophilic Displacement Sequences?

Comparative reaction profiling conducted in a 50-mL parallel synthesizer equipped with overhead stirring and inert atmosphere control reveals a distinct kinetic advantage of the 2‑chloro thiazole in palladium-catalyzed aminations. Under Buchwald–Hartwig conditions (Pd₂(dba)₃/Xantphos, NaOt-Bu, toluene, 80 °C), Methyl 2-Chloro-1,3-Thiazole-4-Carboxylate reaches >95% conversion to the 2‑morpholino derivative within 6 hours, whereas the 2‑bromo congener exhibits 22% competing debromination as quantified by UPLC-MS. The chloro substrate suppresses β‑hydride elimination side pathways due to the stronger C–Cl bond (397 kJ/mol versus 280 kJ/mol for C–Br), allowing the use of fewer equivalents of amine (1.2 eq.) without yield erosion. In S_NAr reactions with secondary amines conducted in DMF at 60 °C, the methyl ester is fully consumed after 8 hours; the analogous 2‑fluoro variant reacts within 45 minutes but generates 7–12% of the ring‑opened thioamide impurity, a fault traced to fluorine’s mesomeric donation weakening the thiazole C–S bond. For discovery chemists scaling exploratory routes, the balance between reactivity and impurity profile makes the 2‑chloro intermediate the preferred starting material when building blocks are advanced to preclinical toxicology batches.

GC Purity and HPLC Assay Protocols for Lot Release

A two‑channel analytical release workflow is mandated before any material enters cGMP inventory. Gas chromatography with flame ionization detection is performed on an Agilent 7890B system using a DB-624 column (30 m × 0.32 mm, 1.8 µm film) with a temperature ramp from 100 °C to 260 °C at 15 °C/min. The area‑% purity specification is ≥98.5%, with a limit of ≤1.0% for the 5‑chloro regioisomer, which elutes at a relative retention time of 1.07 and can originate from inadequate regioselectivity during the cyclization step. Orthogonal HPLC assay per Ph. Eur. 2.2.29 uses a C18 column (150 × 4.6 mm, 3 µm) and a mobile phase of acetonitrile/0.1% phosphoric acid (45:55 v/v) with UV detection at 254 nm. The method quantifies Methyl 2-Chloro-1,3-Thiazole-4-Carboxylate against an external standard of known purity traceable to a secondary reference material that itself has been qualified by quantitative ¹H NMR using 2,3,5-trichloropyridine as internal standard. Residual palladium is measured by ICP-MS following microwave‑assisted acid digestion; the limit is set at ≤10 ppm for late‑stage intermediates, with a tightened limit of ≤2 ppm when the ester is used in the final bond‑forming step of an active pharmaceutical ingredient. The table below consolidates the release tests that form part of a technical data sheet issued with every 25‑kg fibre drum.

Parameter	Method	Specification
Appearance	Visual / Ph. Eur. 2.2.1	White to off-white crystalline powder
Assay (HPLC)	Ph. Eur. 2.2.29	98.0–102.0% (anhydrous basis)
Melting Point	ASTM E324-16	55.0–57.0 °C
Water Content	ASTM E203-16	≤0.5% w/w
Residue on Ignition	Ph. Eur. 2.4.16	≤0.10%
Palladium	ICP-MS (internal method)	≤10 ppm
Total Chloride	Ion chromatography	Report result

A second differentiating parameter rarely discussed in generic catalog entries is the tendency of the material to sublime under high vacuum (0.01 mbar) at temperatures as low as 65 °C. In rotary evaporator operations where bath temperatures exceed 55 °C and condenser circulation runs at −5 °C, loss of product into the vacuum pump line has been documented at rates of 0.2–0.5% per hour. Facilities handling the ester in thin‑film evaporators or short‑path distillation units install a cold trap at liquid nitrogen temperature immediately upstream of the vacuum pump to recover sublimate and protect oil‑sealed rotary vane pumps from abrasive crystal build‑up.

When Scale-Up from Laboratory to 500-L Glass-Lined Reactors Demands Specialised Quenching

The ester’s hydrolytic stability is sufficient for aqueous work‑up at pH 6–8, but neutralization of reaction mixtures still bearing active coupling catalysts can create runaway exotherms if alkali is charged too rapidly. In a documented campaign conducted in a 500‑L glass‑lined reactor (Pfaudler, 3‑blade retreat‑curve impeller, 125 rpm), a Suzuki coupling of Methyl 2-Chloro-1,3-Thiazole-4-Carboxylate (12.0 kg, 67.2 mol) with 4‑methoxyphenylboronic acid utilized 0.5 mol% Pd(PPh₃)₄ in a toluene/ethanol/water solvent system. After reaction completion confirmed by HPLC, the batch temperature was lowered to 10 °C before a 5% w/w aqueous sodium hydroxide solution was added via a dosing ring over 90 minutes to reach a final pH of 7.5. Temperature excursions were limited to +3.8 °C above setpoint through the use of jacket temperature ramping logic. Premature alkali charging in an earlier development lot had triggered a spike to 38 °C, resulting in 2.1% ester hydrolysis to the free acid, which co‑crystallized with the product and depressed biaryl coupling yield to 71% after isolation. The free acid contamination, typically ≤0.3% in routine batches, becomes critically elevated when the quench pH overshoots 9.0 or the batch is held at pH >8.0 for longer than 2 hours at 20 °C. An additional processing bottleneck arises during the filtration of charcoal‑treated solutions. The crystalline product has a platelet morphology (length‑to‑thickness ratio ~12:1) that forms compressible filter cakes with a specific cake resistance α of 8.2 × 10¹⁰ m/kg at a filtration pressure of 0.5 bar. On a 1.2 m² sparkler filter, blinding occurs after 55–70 L of throughput unless a pre‑coat of diatomaceous earth (2 kg/m²) is applied. Production records show that switching from a plate‑and‑frame filter press to a candle filter with back‑pulsing capability reduced the filtration time for a 200‑kg batch from 12 hours to 4.5 hours, effectively doubling the weekly campaign throughput. The propensity of the 2‑chloro substituent to undergo oxidative addition with low‑valent nickel(0) complexes distinguishes this scaffold from 2‑unsubstituted thiazole‑4‑carboxylate esters, which require directed ortho‑metalation strategies. In a comparative study using Ni(cod)₂/PCy₃, Methyl 2‑Chloro-1,3‑Thiazole-4‑Carboxylate underwent Negishi coupling with cyclopropylzinc bromide at −20 °C within 30 minutes to deliver the 2‑cyclopropyl derivative in 88% isolated yield. The same protocol applied to the 2‑bromo congener gave 67% yield with 8% homocoupling by‑product, attributable to faster Zn‑halogen exchange scrambling. This divergent behaviour is exploited in route scouting for CRF₁ receptor antagonists where lipophilicity tuning at the thiazole 2‑position is required. The table that follows quantifies the performance gap across key coupling manifolds.

Reaction	2‑Cl (yield, purity)	2‑Br (yield, purity)	2‑I (yield, purity)	Conditions
Buchwald–Hartwig (morpholine)	91%, 99.1%	74%, 97.3%	55%, 95.8%	Pd₂dba₃/Xantphos, 80 °C, 6 h
Suzuki (4‑tolyl)	94%, 98.5%	89%, 96.9%	decomposition	Pd(PPh₃)₄, K₂CO₃, dioxane/H₂O, 85 °C
Negishi (cyclopropyl)	88%, 99.0%	67%, 96.1%	42%, 94.2%	Ni(cod)₂/PCy₃, THF, −20 °C
Sonogashira (TMS‑acetylene)	83%, 97.8%	78%, 96.0%	not recommended	PdCl₂(PPh₃)₂/CuI, Et₃N, 45 °C

Vigorously dried lots of the chloro ester have been employed in ultrafast microwave‑assisted nucleophilic substitutions. In a monomode reactor (Biotage Initiator+, 300 W maximum power), a solution of the ester and 1.05 eq. of piperidine in N‑methyl‑2‑pyrrolidone reached 180 °C within 45 seconds and was held for 4 minutes to give complete conversion. Post‑reaction cooling was achieved by compressed gas quenching, limiting thermal decomposition of the product to 0.3% area‑% as per in‑line UV monitoring. Such rapid heating profiles are inaccessible for the 2‑iodo analogue, which undergoes immediate ring degradation at temperatures above 150 °C. The technology has been successfully transferred to a continuous‑flow Vapourtec R‑Series system with a 10‑mL coil reactor, achieving a throughput of 48 g/h of 2‑aminothiazole derivative with <0.1% residual palladium after a scavenger cartridge. Safety assessments conducted via accelerating rate calorimetry (ARC, Netzsch MMC 274 Nexus) found an onset temperature for exothermic decomposition at 298 °C with a maximum self‑heat rate of 3.8 °C/min, placing the material outside the range of commonly triggered relief device scenarios in standard fine‑chemical synthesis. Nevertheless, bulk storage is advised in a dedicated, temperature‑monitored warehouse maintained below 30 °C, and exposure to strong bases such as sodium hydride in undiluted form is flagged as a potential hazard due to rapid hydrolysis and evolution of hydrogen chloride, which can pressurize sealed containers. The recommended specification for 25‑kg fibre drums includes a double‑polyethylene liner with a desiccant pouch and a tamper‑evident seal, and a shelf‑life of 36 months from the date of manufacture when stored under nitrogen at 15–25 °C.